So they whipped out vaccines for  COVID-19 in under a year, right?

And meanwhile HIV has been a global menace  for decades and there’s no vaccine in sight. So, what gives?

But the COVID-19 mRNA  vaccines were a special case. And it’s a fact that  stereotypes and discrimination held up funding for HIV  research in the early days. But the honest truth is that lots of people  really, really want to make a vaccine for HIV and the pesky virus makes it  really, really, REALLY hard to do.

Yet researchers haven’t given up, and if anything, the success of COVID vaccines has only  injected new hope into their search. By harnessing biology both  in your body and in the lab, scientists have all sorts of tricks to try  in the search for a vaccine against HIV. [♪ INTRO] Getting diagnosed with HIV used to be  a death sentence, but it isn’t anymore! People with HIV can now live long, full lives thanks to highly effective treatments  in the form of antiretroviral therapy.

We even have reliable prevention in the form of pre-exposure prophylaxis, or PrEP for short. But it’s not recommended for  everyone, only those at high risk. But what would be really sweet is a nice little one  and done jab in the arm for absolutely everybody, so we can put a stop to the over a million  new HIV diagnoses worldwide every year.

But developing an HIV vaccine has not been easy. There have been many clinical trials  representing various attempts, with the earliest trial starting  all the way back in 1987. But so far, none have shown enough success  to be given the FDA stamp of approval.

It turns out, the biological nature of HIV makes  it especially challenging to vaccinate against. In general, when a pathogen enters  your body, or when a vaccine introduces a version of it, your immune system  makes antibodies to fight it off. But with HIV, that immune response  just… doesn’t really happen.

When HIV enters your body, it wraps itself  in a trench coat of sugar molecules, shielding its proteins from being  detected by your immune system. This allows it to slip past your natural  defenses without triggering the alarm. Then, HIV turns the tables and dismantles  the cells of your immune system that were supposed to defend against it.

And as a second layer of disguise, many of the HIV proteins mimic  human immune cell proteins. Meaning a vaccine targeting those viral proteins might direct your immune system  at your own cells by mistake. As if all that wasn’t challenging enough,  HIV is also a notorious shape-shifter.

It mutates quickly, even within the same  person, which means that any antibodies that you might have created against one version  may no longer work after a few mutations. That is, almost any antibodies. Since the early 2000s, much of the  focus for an HIV vaccine has been on a class of antibodies called broadly  neutralizing antibodies, or bnAbs for short.

The B cells of your immune system  are the ones in charge of making all of your antibodies, with each B cell  specializing in one specific antibody. But new B cells are pretty much randomly  mixing and matching antibody genes. Your immune system’s not  waiting around for a pathogen to show up and design it a  perfectly custom antibody.

There is a method to this madness. Randomly generating as many different B  cells as possible maximizes the chance of at least one of those guys getting a match  that’s close enough to grab onto the pathogen. Once a B cell matches with a pathogen, it  will begin spitting out a bunch of antibodies.

Since the initial fit might not have been perfect, those antibodies will get mutated  further to try and improve the match. Even then, those changes are  still random, so your B cells make a lot of duds in order to find the  antibodies that are actually better. So HIV bnAbs happen when your  immune system hits the jackpot and manages to make antibodies against  a less variable part of the virus.

So they can bypass its shape shifting  and work against more versions of HIV. And bnAbs are produced naturally in 10-25% of  people living with HIV, but they aren’t perfect. Even if you do have them, there aren’t  usually enough bnAbs in your body to neutralize all of the virus on their own.

And there may be a good reason why we don’t  usually have too many of them at the ready. bnAbs are known to show some autoreactivity, meaning that they may be primed to  target some of your body’s own cells. In general, that’s seen as  a bad thing for antibodies, because you don’t want your  immune system to attack you. So your body has checks in place  to destroy autoreactive B cells before they can fully develop.

But some of the bnAbs that are the best   at neutralizing HIV also tend  to have more autoreactivity. In fact, some research suggests that  the development of anti-HIV powers comes at the inherent cost of picking  up some autoreactive mutations. And this creates a bit of a catch-22: The  better the bnAbs, the more autoreactivity.

But that means any bnAb-producing B cells you have might get nuked by your body  before they ever mature. And that includes B cells developing  in response to a vaccine. This has made it really difficult for vaccines  to drum up enough bnAb activity to tackle HIV.

Some researchers have found some success  in stimulating the natural precursors that create bnAbs, rather than  trying to get to the bnAbs directly. Scientists wanted to see  if they could get a vaccine to switch on the specific B cells  that go on to make bnAbs against HIV. A phase-1 clinical trial published  in 2022 provided a proof-of-concept that stimulating more bnAb precursors with  a vaccine might be feasible in humans.

This study only looked at  people not living with HIV, but the vaccine did successfully stimulate  a type of B cell that makes bnAbs! However, there are some challenges to overcome before we can develop this strategy further. Basically, the strategy wasn’t  specific enough to turn on only the kind of B cells that make bnAbs.

It might also switch on other B cells willy-nilly. But while scientists tinker away  at optimizing bnAb technology, there’s another angle that people  are looking at for an HIV vaccine. The COVID-19 pandemic granted fame  and glory to the mRNA vaccine.

And it’s inspired high hopes that we  might be able to use that same technology and apply it to different  diseases – including HIV. mRNA refers to a little piece of genetic   information that tells your  cells how to make a protein. Unlike traditional vaccines that deliver  viral proteins directly to your body, mRNA vaccines deliver the  instructions to make viral proteins. Once the mRNA gets in, it marches right on  into your cells’ protein-making factories, and the viral protein gets  translated along with all the others.

Then, once the viral protein is made, it can be presented to your immune  system to trigger antibody production. Since your body is much better at making  proteins naturally than we can in a lab, this is a great tool to leverage against  the diverse and complicated proteins of HIV. It’s also much faster, safer, and more  cost-effective than traditional vaccine types.

Part of the reason why mRNA vaccines  were such a breakthrough for HIV is that our traditional vaccine  options really are not options. Vaccines with a weakened form of the  virus have a tiny chance of accidentally causing the disease, and since HIV is  a chronic disease that has no cure yet, even that tiny chance is  considered way too unsafe. And vaccines that packed a  completely killed version of HIV didn’t generate enough of  an immune response to work.

So, enter mRNA vaccines. Since they don’t contain any actual virus,  there’s no way to accidentally cause the disease. And since mRNA molecules are easy to pack, you can pack the instructions  for a bunch of different proteins all into one vaccine way more easily  than you can with traditional approaches!

And this is important because  targeting just one HIV protein doesn’t produce a strong enough immune response. So, once again, mRNA vaccines are awesome for producing a robust immune response against all the various proteins  that are on the surface of HIV. …In theory. In practice, it's again proving trickier.

A group of researchers across North  America conducted an initial test of an HIV mRNA vaccine in  rhesus macaques and mice. They found that packaging the mRNA for  two different proteins into one dose got a significantly better immune response  than either of the proteins alone. This vaccine was able to induce bnAb  production in the rhesus macaques, and the monkeys successfully made new  immune cells in response to HIV exposure.

Unfortunately, this doesn’t mean it’s ready to go into human arms just yet. While the vaccine did get an immune response, the level of response wasn’t high  enough to count as fully protective. Plus, this protocol included more than  seven injections in total, which is just… way too many to be practical.

And even though HIV mRNA vaccines  have shown promise in animal models, they seem to lose momentum when  translating to human participants. In 2022, three clinical trials were launched to test an mRNA vaccine to protect against HIV. And while the results of these phase 1 trials are not yet published, as of writing this episode, there  have been some initial concerns over some participants experiencing itchiness  and hives after receiving the vaccine.

So there’s a bit of a slowdown while the  researchers try to figure out what’s up. Even though itchiness might not be the worst  side effect that could possibly happen, phase 1 trials are all about establishing safety. The researchers want to make sure that  they understand as much as they can about why these skin effects  are happening before moving on.

So far, all of these vaccines that  we’ve discussed have been preventative, but what about people who  are already living with HIV? Therapeutic vaccines are also in the works, with the goal of stimulating antibodies  after having already acquired HIV. The hope is that the body can  retroactively develop the immune cells to destroy any of the virus that’s hanging around.

While none of the tested therapeutic  vaccines have worked perfectly yet, there’s been a few promising findings. One research group in Europe  tested out a therapeutic vaccine on 45 participants with HIV in a  double-blind, placebo-controlled study. After vaccinating the participants,  they put it to the ultimate test by having the participants stop  taking their HIV medication for up to six months and see how well  their bodies could keep the HIV at bay.

And unfortunately, it didn’t seem to work. Well, let’s not be too pessimistic – it didn’t work well enough yet. None of the participants were able to keep their  HIV levels down after pausing their medication.

But the vaccine was able to get  some immune cell activity going, and it didn't cause any major negative effects. So the researchers think it’s still  worth tinkering with this vaccine to see if they can boost that  response to be more effective. The journey to finding a  vaccine for HIV has been long.

This sneaky virus has a lot of tricks up its  tiny little sleeves to try to stay one step ahead of our immune systems, but scientists  are closing the gap every day. With our ever-improving knowledge on bnAbs, we’re working on a solution that can  handle all of the strains of HIV. And the promising track record of mRNA vaccines provides an exciting alternative  to traditional technology.

So, we're tackling this disease from  multiple angles, and with more testing and a few more hurdles to overcome,  we might soon be able to prevent and treat the transmission of HIV for everyone. [♪ OUTRO]